. . . . . •
`
`AN AAPS WORKSHOP
`COSPONSORED BY
`• US FOOD & DRUG
`ADMINISTRATION
`
`•
`
`----
`
`PRINCIPLES AND CRITERIA
`. FOR THE DEVELOPMENT
`AND OPTIMIZATION OF
`
`THERAPEUTIC PRODUCTS
`
`PROGRAM
`
`MARCH 26-28, 1990
`HYATT REGENCY CRYSTAL CITY
`ARLINGTON, VIRGINIA
`
`1111.!
`
`,-
`
`(
`
`1 of 50
`
`Almirall EXHIBIT 2049
`
`Amneal v. Almirall
`IPR2019-00207
`
`

`

`TOPICAL DRUG PRODUCTS
`WORKSHOP
`
`Principles and Criteria for the
`Development and Optimization of
`Topical Therapeutic Products
`
`March 26-28, 1990
`
`This AAPS/FDA/Industry co-sponsored workshop
`will address problems, issues and possible solutions
`in the development and optimization of der(cid:173)
`matological topical drug products.
`
`The major objectives of the workshop are to:
`
`• Review and evaluate available information
`on topical drug products.
`
`• Evaluate relationships between phar(cid:173)
`macological activity, drug delivery and clini(cid:173)
`cal efficacy.
`
`Planning Committee
`
`Steering Committee (Co-Chairmen)
`Distinguished Professor William I. Higuchi
`University of Utah
`
`Dr. Charan R. Behl (Coordinator)
`Hoffmann-LaRoche, Inc.
`
`Dr. Vinod P. Shah
`Food and Drug Administration
`
`Advisors
`Dr. A. Waseem Malick
`Hoffmann-LaRoche, Inc.
`
`Dr. Jerome P. Skelly
`Food and Drug Administration
`
`Dr. Dinesh Sharma
`National Institutes of Health
`
`•
`
`•
`
`Identify important principles in the develop(cid:173)
`ment and optimization of topical drug
`products.
`
`Members
`Dr. Gordon L. Flynn
`University of Michigan
`
`Identify ways to optimize topical drug
`delivery to target sites.
`
`Dr. Sergio Nacht
`Advanced Polymer Systems
`
`• Raise possible concerns related to the local
`and systemic toxicity problems arising from
`optimization of drug delivery.
`
`• Discuss regulatory concerns in the evalua-
`tion of topical drug products.
`
`Dr. Eugene Gans
`Hastings Associates
`
`Dr. Russell P. Potts
`Pfizer Central Research
`
`A second part of this workshop will be held in the
`Spring of 1991. The purpose of the second part
`will be to provide solutions for the problems iden(cid:173)
`tified in the first part of the workshop.
`
`Dr. Shirley Ng
`R.W. Johnson Pharmaceutical Research Institute
`
`Dr. Howard I. Maibach
`University of California, San Francisco
`
`Sponsors
`
`A special thanks to Dr. A. Waseem Malick,
`Hoffmann-LaRoche, Inc., and Dr. Sergio Nacht,
`Advanced Polymer Systems, for their generous con(cid:173)
`tributions in funding the planning costs for Lhis
`workshop.
`
`Dr. Gerald G. Krueger
`University of Utah
`
`Dr. Boyd J. Poulsen
`Syntex Research
`
`Dr. Hans Schaefer
`CIRD (France)
`
`Dr. Maw-Sheng Wu
`The Upjohn Company
`
`-1-
`
`2 of 50
`
`

`

`PROGRAl\tl
`
`Room Assignments
`
`12:05p.m.
`
`General Discussion and Q&A
`
`Registration
`General Session
`Lunch
`Reception/Posters
`
`2C Foyer
`Regency E-F
`Regency C-D Center
`Regency C-D Center
`& 2C Foyer
`
`12:30 p.m.
`
`Lunch
`
`CRITICAL CONSIDERATIONS IN THE
`DEVELOPMENT OF TOPICAL PRODUCTS
`
`Moderators:
`
`A. Wasecm Malick, Ph.D.
`Shirley Ng, Ph.D.
`
`MONDAY, MARCH 26, 1990
`
`1:30 p .m.
`
`Welcome
`Carl C. Peck, M.D.
`Food and Drug Administration
`
`2:15 p.m.
`
`Critical Considerations - I
`Charan R. Behl, Ph.D.
`Hoffmann-La Roche Inc.
`
`Critical Considerations - II
`Russell 0. Potts, Ph.D.
`Pfizer Central Research
`
`3:00 p.m.
`
`Break
`
`3:20 p.m.
`
`4:05 p.m.
`
`Critical Considerations - III
`Brian W. Barry, Ph.D.
`University of Bradford
`(United Kingdom)
`
`Critical Considerations - IV
`Gerald G. Krueger, M .D .
`University of Utah
`
`4:50 p.m.
`
`General Discussion and Q&A
`
`5:30 p.m.-
`6:30 p.m.
`
`Reception
`
`TUESDAY, MARCH 27, 1990
`
`DEVELOPMENT OF TOPICAL DRUG
`PRODUCTS- I
`
`Moderators:
`
`Vinod P. Shah, Ph.D.
`Gerald G. Krueger, M.D.
`
`8:30 a.m.
`
`9:30 a.m.
`
`-2-
`
`Examples of Problems
`Encountered in the
`Determination of Bioavailability
`of Drugs from Topical Products
`Vinod P. Shah, Ph.D.
`Food and Drug Administration
`
`Lynn K. Pershing, Ph.D.
`University of Utah
`
`Clinical Toxicology of Topical
`Products
`Howard I. Maibach, M.D.
`University of California
`
`8:30 a.m.
`
`8:40 a.m.
`
`8:50 a.m.
`
`Scientific Rationale and
`Objectives
`Charan R. Behl, Ph.D.
`Hoffmann-La Roche Inc.
`
`Regulatory Rationale and
`Objectives
`Vinod P. Shah, Ph.D.
`Food and Drug Administration
`
`PROBLEMS IN THE DEVELOPMENT OF
`TOPICAL PRODUCTS
`
`Moderators:
`
`Charan R. Behl, Ph.D.
`Howard I. Maibach, M.D.
`
`9:00 a.rn.
`
`9:45 a.m.
`
`General Introduction and Concep(cid:173)
`tual Evaluation of the Essential
`Differences in Topical and
`Transdermal Drug Delivery
`Gordon L. Flynn, Ph.D.
`University of Michigan
`
`Basic Review of Skin
`Structure/Composition and
`Pathophysiology of the Skin as
`Related to Skin Uptake and Skin
`Metabolism of Topical Drugs
`Hans Schaefer, Ph.D.
`CIRD (France)
`
`10:30 a.m.
`
`Break
`
`10:50 a.m.
`
`11:35 a.m.
`
`Developmental Process in Topical
`Dosage Forms
`Boyd J. Poulsen, Ph.D.
`Syntex Research
`
`Problems and Issues in Review
`and Regulatory Process
`C. Carnot Evans, M.D.
`Food and Drug Administration
`
`3 of 50
`
`

`

`10:00 a.m.
`
`Break
`
`WEDNESDAY, MARCH 28, 1990
`
`PROGRAJ\tl
`
`10:20 a.m.
`
`11:05 a_m_
`
`11:50 a.m.
`
`Pitfalls in Toxicological Studies
`Robert C. Scott, Ph.D.
`ICI/PLC (United Kingdom)
`
`Development of Glucocorticoid
`Products
`Joel A. Sequeira, Ph.D.
`Schering Plough Corporation
`
`Skin Blanching Assays and
`Alternatives
`Dale P. Connor, Pharm.D.
`Uniformed Services University of
`the Health Sciences
`
`12:30 p.m.
`
`Lunch
`
`DEVELOPMENT OF TOPICAL DRUG
`PRODUCTS · II
`
`Moderators:
`
`Gordon L. Flynn, Ph.D.
`Maw-Sheng Wu, Ph.D.
`
`1:30 p.m.
`
`2:15 p.m.
`
`Development of Anti-Infective
`Agents for Skin
`James J. Leyden, M.D.
`University of Pennsylvania
`
`Development of Topical Retinoids
`Thomas J. Franz, M.D.
`University of Arkansas
`
`3:00 p.m.
`
`Break
`
`3:20 p.m.
`
`4:05 p.m.
`
`4:50 p.m.
`
`Hair Growth Products:
`Challenges
`Vera H .. Price, M.D.
`University of California, San
`Francisco
`
`Conventional vs. Controlled
`Release Topical Products
`Sergio Nacht, Ph.D.
`Advanced Polymer Systems, Inc.
`
`Cosmeceuticals
`Eugene H. Gans, Ph.D.
`Hastings Associates
`
`REGULATORY ASPECTS IN THE
`DEVELOPMENT OF TOPICAL PRODUCTS
`
`Moderators:
`
`Jerome J. Skelly, Ph.D.
`Dinesh Sharma, D.Sc.
`
`8:30 a.m.
`
`9:15 a.m.
`
`Factors to be Considered in the
`Evaluation of Bioavailability and
`Bioequivalence of Topical
`Products
`William I. Higuchi, Ph.D.
`University of Utah
`
`Quality Control Aspects of
`Topical Products
`Nicholas Kail, Ph.D.
`CIRD (France)
`
`Vinod P. Shah, Ph.D.
`Food and Drug Administration
`
`10:00 a.m.
`
`Break
`
`10:20 a.m.
`
`International Regulatory Process:
`Presentations and General
`Discussion
`United States - C.C. Peck, M.D.
`Canada - D.W. Hughes, Ph.D.
`Japan - Y. Morimoto, Ph.D.
`Gennany-A. Zesch, M.D.
`France - H. Schaefer, Ph.D.
`United Kingdom - To be
`announced
`
`12:00 noon
`
`Lunch
`
`WHERE DID WE COME FROM, WHERE ARE
`WE NOW, AND WHERE ARE WE GOING?
`
`Moderator:
`
`William I. Higuchi, Ph.D.
`
`1:00 p .m.
`
`Panel Presentation and
`Discussion
`A. Waseem Malick, Ph.D., Roche
`Dinesh Sharma, D.Sc., NIH
`Jerome P. Skelly, Ph.D., FDA
`
`3:00 p .m.
`
`Closing Remarks and Summary
`
`-3-
`
`4 of 50
`
`

`

`L
`
`DEVELOPMENT PROCESS IN TOPICAL OOSAGE FORMS
`
`BOYD J. POULSD, PB.D.
`StNl U USIAI.CB
`PALO ALTO, CA 94304
`
`I. "PRE-DEVELOPMERT•
`A. DRUG PROPERTIES
`1. PHYSICAL CHEMICAL PROPERTIES
`2.PHARMACOLOGY
`
`B. PROPOOED CLINICAL APPLICATION
`
`II. EARLY DEVnOPMiNT nEMENTS
`'A.PROTOTYPE FORMULATIONS
`1. DESIGN APPROACH
`2. DRUG BIOA VAILABILITY (ACTIVITY)
`3. DRUG STABILITY
`4. PIU:SERVATION
`5. FORMULATION TOXICOLOGY
`a. IRRITATION
`b. SENSITIZATION
`
`B. ACCnERATED STABILITY STUDIES
`1. DRUG SHELF LIFE
`2. PldJj£RVATIVE SYSTEM
`3. STABILIZERS
`4. PHYSICAL STABILITY
`5. PACKAGE SELECTION
`
`C. DRUG DRIVERY - IN VITRO EXPERIMENTATION
`
`Ill. ADVANCED DEVELOPMENT STAGE
`
`A. FINAL FORMULATION SELECTION AND EVALUATION
`
`5 of 50
`
`

`

`1. OOSI (CONC.) SELECTION
`2. PRESERVATION SYSTEM
`3. COSMETIC ATI'RIBUTF.S MAXIMIZED
`4.sTABILITY {BOTII CHEMICAL AND PHYSICAL)
`SATISFACTORILY CHARACTERIZED.
`5. FINALIZE FORMULATION
`
`B. PRODUCT EVALUATION
`1. MANUFACTURE AND TEST REGISTRATION
`BATCHES.
`2. SHIPPING TESTS
`3. USE TESTS
`4. SCALE-UP STUDIES
`5. PRODUCT SPECIFICATIONS
`
`C. TECHNOLOGY TRAIISFER
`
`IV. REGISTRATION
`
`V.PRODUCTINTRODUCTION
`
`6 of 50
`
`

`

`( 1) Identify
`
`Disease Target site Receptor site
`
`(2) Estimate Skin Condition
`
`+
`+
`(3) Choose
`~
`Drug Delivery kinetics
`+
`+
`+
`+
`(7) Product Trial F' ormulatlons
`~
`
`( 4) Select F' ormulatlon Type
`
`(5) Isolate Rate-Limiting Step(s)
`
`(6) Choose Ingredients
`
`Thermodynamic control? Penetration enhancer?
`
`Both approaches?
`
`+
`
`(9) Test the Formulations
`
`lnv i t t \v i~
`
`simple releas~Oll'er skin
`
`animals
`
`volunteers
`
`+
`+
`
`( 10) Clinical Trials
`
`.
`
`( 11) Review All Data
`
`Flgure 12 Steps In a progrom for optimizing a toptoal drug formulation
`
`...,,,,, a.Ir., •~ llrft(cid:127) toHU .0.J .... (cid:127) la
`AR(cid:127) ta••• ........ IMJ ....... Ull Jldl1al,
`• UI-Sll lllS.
`~ ..,_ ,-.
`
`7 of 50
`
`

`

`SIMPLIFIED DEVELOPMENT SCHEMATIC
`
`FORMULATION STAGE
`
`ACTIVITY/ OBJECTIVE
`
`Predevelopment
`
`Pharmacology
`
`Experimental
`Formulation
`
`Acute Toxicology
`
`Phyalcal-Chemlcal
`Characterization
`(Preformulatlon)
`
`Simple Delivery Systems
`
`Evaluate Drug/ System
`Stability
`?'hC<.11 ~o.W..Ot'
`Clinical ~cal (Dose
`Response, Human
`Tolerance, etc.
`
`Model Studlea to Support
`Formulation Selection
`On Vitro and In VNd
`
`8 of 50
`
`

`

`SIIIPURED DEVELOPAfENT SCHEMATIC fCont'dJ
`
`FORMULATION STAGE
`
`ACTIVITY/ OBJECTIVE
`
`''Prototype"
`Formulations
`
`Final Product
`
`Select Drug Cone.
`
`Preservative System
`
`Continuing Tox Studies,
`Animals and Human
`
`Phase II Clinical Studies
`
`Select Drug Cone.
`
`Chronic Tox, Two
`Species
`
`Phase 3 Clinical
`
`Final Packaging
`
`Product Scaleup
`
`Registration Batchee
`
`Registration/ Final
`Product Specs.
`
`9 of 50
`
`

`

`MECHANISM OF DEGRADATION z
`
`o_._.<o<mwmn_".0Ew_z<:UwE
`
`NOA
`
`(Dz
`
`DEGRADATION PRODUCTS
`
`
`
`”roan—Omn—ZO_._.<D<m—0mo
`
`DEVELOPMENT
`
`hzmlm04m>mo
`
`STABILITY SUPPORT
`
`
`
`hmOn—n—Dw>._._.=m<._.m
`
`CRYSTALLINE MODIFICATIONS II
`
`
`
`=m20_._.<o_u=002mz_._.._<._.m>mo
`
`I PREFORMULATION ~
`
`ZO_._.<.._DEm_Ou_m—"_n_
`
`
`
`------PREDEVELOPMENT
`
`sz2m04m>mommm
`
`DEPARTMENT ACTIVITIES
`
`
`
`mm_._._>_._.0<._.Zm_2._.m_<n_mo
`
`. IND
`
`
`
`
`
`Dz..zo_h<:._<>m
`
`EVALUATIOJ
`
`ll...
`
`I
`BASIC RESEARCH
`I
`
`Iom<mmmm293
`
`DRUG DEVELOPMENT
`
`
`
`._.Zm_s_n_0._m>m_nGama
`
`10 0f50
`
`10 of 50
`
`
`
`

`

`• CHEMICAL REACTIVITY
`
`• PHYSICAL PROPERTIES
`
`• ANALYTICAL METHODS
`
`SALT SELECTION ~~~
`.-fS' ½~J> \s
`
`•
`
`PREFORMULATION STUDIES
`
`IN EVALUATION PHASE
`
`{
`
`(
`
`11 of 50
`
`

`

`f
`U) ·-~
`
`Q)
`
` u
`
`--I
`
`
`
`products
`hydrolysis
`
`(cid:141)
`
`9
`
`7
`
`pH
`5
`
`3
`
`1
`
`...., ..
`c-----7r 'aG-l1Nf' ~=(cid:173)
`
`· · ·· ·· ·· ·~ -
`· ·
`
`-9
`
`-7
`
`-5
`
`-
`
`-3 I
`
`~H
`~HOH ~H2CH2COOH
`
`1
`
`~Hl
`CHCNHCHCNHCHCNH2
`
`NHCOCH1
`
`OH
`
`0
`
`II
`0
`
`II
`0
`, o~
`
`II
`0
`
`HO
`
`5, 528 (1988)
`Pharmaceutical Res.
`M. F. Powell, et. al.
`
`KINETICS OF DEGRADATION
`
`i
`
`/
`
`(
`
`12 of 50
`
`

`

`Time (days)
`
`60
`,
`
`,
`
`50
`,
`
`,
`
`40
`,
`
`,
`
`JO
`,
`
`20
`,
`
`IO
`,
`
`,
`
`0
`ol
`
`Unpublished Results
`H. T. Nguyen and T. W. Chan
`
`3
`R = (CH ) CH
`
`2 3
`
`R = COCH3
`
`20
`
`40
`
`60
`
`80
`
`100
`
`120
`
`OR 50 / 50 PG / Water
`
`ococ~
`
`% Rem
`
`Stability of Napthoqulnones
`
`In a Model Cream
`
`(cid:141)
`
`so0c
`
`OR
`
`OCOCH:J
`I
`
`Cl
`
`PREDEVELOPMENT
`
`SCREENING
`
`\
`(
`
`(
`
`(
`
`13 of 50
`
`

`

`Solid-State Stability
`Hygroscoplclty
`Phase Conversion
`
`I EARLY EVALUATION CRITERIA~
`
`Amorphous
`Clathrates
`Solvates
`Hydrates
`Polymorphs
`
`IDENTIFY
`
`Ethyl Acetate
`Acetone
`2-Propanol
`Methanol
`Water
`
`RECRYSTALLIZE FROM
`
`CRYSTALLINE MODIFICATIONS
`
`14 of 50
`
`

`

`om
`
`-Effective Thickness of the Skin Barrier
`
`h
`
`-Concentration of Drug Dissolved in the Vehicle
`
`Cv
`
`PC -Effective Partition Coefficient of Drug Between Skin Barrier
`
`and Vehicle
`
`-Effective Diffusion Constant of the Drug in Skin Barrier
`
`D
`
`dt
`~ -D(PC)C,
`
`h
`
`DRUG-VEHICLE-SKIN INTERACTIONS
`
`(
`
`15 of 50
`
`

`

`Drug Concentration In Vehicle
`
`c.
`
`~
`
`Rate
`Penetration
`
`.11e.a,I 1y1-fi--M~-0kc-+n>½"t1 .-~ ~
`
`(
`
`16 of 50
`
`

`

`Percent Solublllzer
`
`0-Wl
`
`dt
`!IQ• PC•C,O.
`
`h
`
`lbrualum
`
`cl
`~ • (AR,C, )1/2
`·1rug&uapenelon
`
`2t
`
`cl
`!19 • c ( IL )111
`8olutlon
`
`• nt
`
`.,
`
`Skin -Rate Limiting
`
`Vehicle -Rate Limiting
`
`1
`
`(
`
`(
`
`(
`
`17 of 50
`
`

`

`~
`
`of system instability).
`degree of partial solubilization, the greater the probability
`which the drug is partially solubilized. (The greater the
`Better to cut your wrist than develop a formulation in
`
`FORMULATION RULE NUMBER 1
`
`(
`
`(
`
`(
`
`18 of 50
`
`

`

`()tag
`
`-Drug and Vehicle Characteristics
`-Method of Application
`-Area of Application Site
`-Condition of Skin
`-Application Site
`
`Drug Absorption Depends on MttnY Factors
`
`-Thlckneaa of Applied Vehicle
`-Frequency
`-Application Area
`
`Total Quantity of Drug Administered Varies Greatly
`
`CHARACTERISTICS OF TOPICAL DRUG ADMINISTRATION
`
`(
`
`(
`
`\
`
`19 of 50
`
`

`

`0.
`
`• Precipitation of Drug or Other Vehicle Components
`
`• Emulsion Breakage or Inversion
`
`Influx of Skin Fluids Into Vehicle
`
`•
`
`• Losa to Bandages or Clothing
`
`• Sorption or Absorption of Vehicle Components
`
`• Losa of Volatile Components from Vehicle
`
`Potential Vehicle Changes Following Application
`
`(
`
`(
`
`(
`
`20 of 50
`
`

`

`DEL I VERY DY NAM I CS
`....... - ......................... ·"
`- .....
`. . . . . . , . . . . . . . , . . . . . . . . . . . . . . . . .
`• • .. .. ..
`. ............ - ..•••••••••••• APPLIED
`.,,·.•.•••••••• au,-... ••••••: :au sea :o
`. . . . . . . . . . . . .. .. . . . . . . . . . . . . . . . . . . .
`. . . . . . . . . . . . . . . . . . . . .
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`· .•••••••••••••••••••••.•••••••• PHASE
`. . . . . . . . . ,
`. ....
`. . . .
`s.c.
`·.· ... •,-.•,•.~--- - -
`· .. ·
`• •••
`•
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`DERMIS
`
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`
`t = )(
`
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`• . . .
`•
`
`•
`
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`
`-.
`
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`•• • . . ..
`
`1. APPL I CAT ION LA VER SHRI NICS - SOL VENTS EVAPORATE
`ANO ALSO O I FFUSE INTO SK IN.
`2. DRUG CONCENTRATION IN APPLICATION LAVER INCREASES.
`3. VEHICLE COMPONENTS AFFECT SKIN BARRIER - CHANGES
`IN PC ANO O?
`4. DEPLETION OF DRUG FROM LAYER OIRECTlV ABOVE LESION
`OCCURS.
`
`21 of 50
`
`

`

`~'-; Q,
`~~
`
`~
`-,J
`~
`"
`DELI VERY DY NAM I CS (CONT.) --J,/')
`
`..,
`t5-\
`
`t = 2X
`
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`
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`
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`' ..
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`. •·•
`
`1. VEHICLE EBR I AND DRUG CRVST Al.S REMAIN
`ON SK IN SURF ACE.
`2. DRUG DEPLETED FROM REGION OF LESIONS.
`3. DIFFUSION CONTINUES AT REDUCED RATE THROUGH
`NORMAL, INT ACT SKIN.
`
`22 of 50
`
`

`

`,_
`
`"?
`
`7 -<
`-i
`~ .,;
`,_ ¾J
`~ -~
`-+ ·-
`
`<?S
`
`-f.--·
`~~
`
`,s-"'\<
`
`h < C o
`
`‘4. My“
`
`as
`as
`CD
`a:
`~ <
`... as
`(cid:127)--C.
`C.
`.
`<
`<
`
`C
`0
`.5
`(cid:127) -
`as
`0
`
`o E a
`
`-
`
`an.
`_. “fw‘m .1
`
`r,:
`
`, Jo( ...
`
`-.,[,·
`
`~ -0
`
`23 0f 50
`
`23 of 50
`
`

`

`o E a <
`
`a,
`cu
`
`mh < C o
`
`C:
`
`.,;:.,.. ·
`
`... : .
`
`a, ...
`<
`0 ·-+ii a,
`0 ·--C.
`C.
`<
`
`.3
`cu
`
`0
`
`24 0f 50
`
`24 of 50
`
`

`

`20.00%k020=§2m0200k0SukkmWE
`“20:52::
`22whé180$:205E0032000133.32‘
`
`i.60:93.2.30..._i..oonEucm:—coaches-.00
`
`
`
`.3:$35».&
`
`25 0f 50
`
`25 of 50
`
`

`

`ICBIAUJG AND BYNALAR CREAMS: ~
`o, 11180C0118.HJC'l10N 8COIIR llf CQ11Cl!NIJIAJJ0fl
`
`KENALOGCREAMS
`
`Formulation
`
`Total VC Score 1
`
`0.025%
`0. ff.
`0.5%
`
`54
`58
`54
`
`SYNALAR CREAMS
`
`Formulation
`
`Total 'JC Score1
`
`0.01%
`0.025%
`0.21.
`
`28
`48
`71
`
`1No atatl8tlcally significant dlfferancea found
`2 All statiatlcally different (P < .06)
`
`AJt-, a, •' 1 ·~ •••• llllll Wrrlllci. ~ .. AMI. Da ••• ,. 1JS.
`lSlf(lfn).
`
`26 of 50
`
`

`

`'----..,-/
`
`-----
`
`...
`...
`CJ
`C
`-
`z
`a:
`-a:
`w
`a:
`C m
`•• z -=-: en
`~ • 0 z
`
`
`
`
`
`
`
`._.O<._.z_cmE¢<m"2354<I¢Oz
`
`-I
`C
`
`CC
`0 0
`
`QJ
`
`·- -•• CC
`• a. a. •• ~ ~
`...... QQ
`.... ~
`
`u,u,
`QQ
`~ ~
`
`..- N
`II
`II
`cm
`.... ••
`EE
`••
`>ii >ii
`en en
`
`coficunmam5:5Q.9u<523m
`
`:o_a:onm:m9.5isua583m
`
`~
`)C
`
`V1· .. .....,.
`mm
`II
`II
`cc
`• •
`)C
`
`
`
`o.waau<63mu<2...“.22m.35
`~ -"-• .. • .. en
`•CJ . :)
`
`>ii ,, ..
`enc
`
`l ..
`
`I
`
`,c
`n•
`
`..
`
`a. u
`
`27 0f 50
`
`27 of 50
`
`

`

`I
`
`AUC: B rv 2 x A (I = x)
`lnltlal Flux: A ~ B
`
`.
`
`t=x
`
`' .
`
`Cp
`
`DISEASED SKIN: BARRIER DAMAGED
`
`(
`
`\
`
`(
`
`28 of 50
`
`

`

`VEHICLE DESIGN:
`
`SOL
`
`FLUX
`
`FLUX
`
`SOLVENT >
`
`C >
`
`SOLVENT >
`
`-
`
`-
`
`-
`
`-
`
`-
`
`-
`
`-
`
`-
`
`-
`
`- ENHANCEMENT
`
`FLUX
`
`---~
`
`- OPTIMIZATION
`
`SOLVENT >
`
`1113'\
`
`29 of 50
`
`

`

`(I)\ fr011 Propylene Glycol-water Gels at 37•c.
`Fluocinon1de Acetonide (A) and 1ts 21-Acetate Ester, fluoctnon1de
`FIGURE 3. Effect of Propylene Glycol Concentration on the Release of O.OZSI
`
`~ PROPYLENE GLYCOL IN GEL
`0
`100
`
`20
`
`% PROPYLENE GLYCOL IN GEL
`
`100
`
`80
`
`60
`
`40
`
`20
`
`0
`
`80
`
`60
`
`40
`
`~ 1
`.....
`c(
`...J
`a:
`w
`~ 2
`c(
`UJ en
`ri
`E
`03
`.
`
`4
`
`(8)
`
`(A)
`
`ACETATE RELEASE FROM PROPYLENE GLYCOL-WATER GELS AS A
`
`FLUOCINOLONE ACETONIDE AND FLUOCINOLONE ACETONIDE
`
`F(TIME)
`
`(
`
`(
`
`1
`
`0 ....
`.... 2
`c(
`...J
`a:
`...J 3 w
`c( w
`w en
`a
`~ 4
`
`CJ)
`
`5
`
`6
`
`;i,-
`
`(
`
`30 of 50
`
`

`

`•
`J
`
`0
`
`zo
`
`IO
`
`IO
`
`l0Q
`
`...................
`
`.... .. ,.,.,_...., ... h c; UMI _,.. a I G...._ "',.._y 1:111-riictailillla :esp w ( O\.
`':ftO.O:,•~aaa
`. . . . . . ,
`L ,_ . . ._ . . . . . . . . . . . . . (4)1or•
`I
`
`,
`
`.,...,.
`
`$1 · -
`
`31 of 50
`
`

`

`IN VIVO MODEL REQUIREMENTS
`
`32 0f 50
`
`[PREFERRED] LINK TO IN VIVO RESPONSE
`
`•
`• CREDIBLE
`• SIMPLE, REPRODUCIBLE
`
`m._m_ODn_Om_n_mm
`
`uni—ammoo
`
`IN VITRO MODEL REQUIREMENTS
`
`(
`
`(
`
`<
`
`MIKE—mo whzmsfimficmm
`mszmmmm95Z.O...v_z_._Emmmmu—mmEo
`
`
`._.0mn_n_m._<O_z_._0O...v_z_._EmmmmmmmE
`
`
`
`
`m2_._...n_ZDOm<-sz._.m._m<._.n_w00<
`
`Ian—0.2Om._._>z.
`
`WhZMEMEDOmmJuno—2O>_>Z_
`
`0108
`
`DEMONSTRATED
`[PREFERRED] LINK TO CLINICAL EFFECT
`
`om._.<m._.sz_2mo
`
`•
`• ACCEPTABLE TURN-AROUND-TIME
`• CREDIBLE
`• ACCESSIBLE
`
`m._m_wwm0Q<
`
`uni—ammo
`
`11REPRODUCIBLE11
`
`..w4m_03n_0mmmm=
`
`•
`
`32 of 50
`
`

`

`SINCE TOPICAL DRUG ABSORPTION IS USUALLY
`RATE-LIMITED BY THE SKIN BARRIER, ANY .1lL VITRO
`APPROACH TO MEASUREMENT OF TOPICAL
`BIOEQUIVALENCE OF PRODUCTS MUST SIMULATE THE
`ROLE OF .THIS BARRIER TO DRUG ABSORPTION.
`
`33 of 50
`
`

`

`THERE ARE MANY CLINICAL ASPECTS OF TOPICAL DRUG
`ADMINISTRATION THAT ARE DIFFICULT TO INCORPORATE
`INTO ANY .lli VITRO MODEL.
`lHESE INCLUDE:
`
`{l) VARIATIONS IN THE AMOUNT OF APPLIED
`DOSE.
`
`{2) DOSING FREQUENCY
`
`{3) APPLICATION METHOD (OPEN, OCCLUDED,
`DRESSINGS, ETC.)
`
`(4) SKIN CONDITION (DAMAGED, DISEASED,
`NORMAL), AGE AND SITE).
`
`(5) DRUG METABOLISM IN SKIN
`
`34 of 50
`
`

`

`IN VITRO RELEASE MODELS
`
`ADVANTAGES
`
`SIMPLICITY
`SIMPLICITY
`
`MINIMIZES ANALYTICAL DIFFICULTY
`MINIMIZES ANALYTICAL DIFFICULTY
`
`CAN ACCURATELY REFLECT DRUG-VEHICLE INTERACTIONS
`CAN ACCURATELY REFLECT DRUG‘VEHICLE INTERACTIONS
`THAT MIGHT PROMOTE OR RETARD DRUG DIFFUSION.
`THAT MIGHT PROMOTE OR RETARD DRUG DIFFUSION.
`
`DISADVANTAGES
`W
`
`DOES NOT SIMULATE MEMBRANE CONTROLLED PIFFUSION
`DOES NOT SIMULATE MEMBRANE CONTROLLED DIFFUSION
`NOR REFLECT VEHICLE-INDUCED MEMBRANE EFFECTS.
`NOR REFLECT VEHICLE-INDUCED MEMBRANE EFFECTS.
`
`USUALLY DOES NOT SIMULATE VEHICLE APPLICATION
`USUALLY DOES NOT SIMULATE VEHICLE APPLICATION
`INCLUDING EVAPORATION OF SOLVENTS, ETC.
`DYNAMICS,
`DYNAMICS.
`INCLUDING EVAPORATION OF SOLVENTS. ETC.
`
`35 of 50
`
`35 of 50
`
`

`

`IN YIIRC SKIN PIEEUSIQN {FINITE PCSEl
`
`ADVANTAGES
`
`PERMITS USE OF EXCISED HUMAN SKIN
`
`ALLOWS REALISTIC SIMULATION OF CLINICAL USE
`CONDITIONS.
`
`UISAPYANTAGESIPROBLEMS
`
`LIMITED AVAILABILITY OF EXCISED HUMAN SKIN.
`
`VARIABILITY* OF- EXCISED HUMAN SKIN RE
`PERMEABILITY PROPERTIES.
`
`MEASUREMENT OF MANY DRUGS DIFFICULT DUE TO LOW
`FLUX RATES.
`
`LACK OF DEFINITIVE CORRELATIONS BETWEEN HUMAN
`SKIN AND OTHER ANIMAL SKIN.
`
`LIMITED INFORMATION REGARDING DISEASE EFFECTS ON
`SKIN PERMEABILITY.
`
`36 of 50
`
`

`

`stirrer
`
`ehicle layer
`
`boundary
`layer
`
`DIFFUSION PROFILES AS A f (TIME):
`boundar, layer
`
`, ••• ,.01,
`+
`
`. ......
`
`..... , .. ~····
`
`> ... -> -... 0
`<
`0 -~
`< z
`>
`C
`0
`~ a:
`w
`J:
`I-
`
`.. ..
`
`a.:
`
`• ••
`
`,,, .. ,. ..
`
`,.
`
`DISTANCE FROM SOURCE
`
`FIGUIE 11. Schematic Representation of a Ffnfte Dose System (top) and
`
`Diffusion Profiles as a Function of Time (bottom) •
`
`.
`
`37 of 50
`
`

`

`INCREASINGLY
`
`>I_GZ_w<mmoz_
`
`• PERMEABILITY -EXCISED HUMAN SKIN -FINITE DOSE
`• PERMEABILITY -EXCISED HUMAN SKIN
`• PERMEABILITY -HUMAN STRATUM CORNEUM
`• PERMEABILITY -EXCISED ANIMAL SKIN
`• ARTIFICIAL MEMBRANE DIFFUSION
`• RELEASE -GELLED MIXED SOLVENTS INTO 1PM
`• P.C. -MIXED SOLVENTS VS ISOPROPYL MYRISTATE
`• SOLUBILITY DETERMINATIONS, MIXED SOLVENTS
`
`38 0f 50
`
`IN VITRO EXAMPLE:
`
`um_I_n=)_¥.xm
`
`\
`/
`
`\
`
`I
`
`Om._._>Z_
`mwODm._._Z_.I_IZ_v_wZ<S_D_I_Gum—oxmI>._._.=m<ms_mwn_
`
`
`
`
`m._.<._.w_m>24>n_0mn_0w_w>whzm>40waux:I.O.n_
`
`
`
`whzm>40waux—.2.wZO_._.<Z_S_mm._.mn_>._._I=mDJOw
`
`
`
`En:O._.z_mhzm>40wDmx=2DMIEmGImw<mgmm
`
`
`
`SSMZEOOEquEhw2.223....I>._._.=m<m_2mwn_
`
`
`
`
`
`
`Z_v_wI._<S=Z<owwfixmI>._._4_m<m2m_mm
`
`
`22wZ<§DImeaxmI>._._.=m<m§mwn_
`
`
`ZO_wD.I_.I=n_wz<mm2m2.._<_O_.I=._.m<
`
`RELEVANT .
`
`_.Z<>m.dmm
`
`0107A
`
`38 of 50
`
`

`

`om
`
`~,. 245-249, 1915.
`"'ltaatta#u Aiso,zdo•, 11'.: llrouql al M.INm~ Miami Dekur, bu:.,
`A/la Wata al Mldl,uj, "b, J'no Paalta#u Alsor,tlo• Mea.,...,,,...,
`
`-Clinical Studies ( i . e. , Scholtz-Dumas Psoriasis Assay)
`-----------------------------------------------------------------------------
`-"Absolute" Topical Bioavailability
`-Blological/Pharmacologic Response
`-Surface Disappearance
`-Surface Recovery
`-Radioactivity in Blood
`-Radioactivity in Excreta
`
`In Vivo Methods
`
`\
`
`(
`
`39 of 50
`
`

`

`• TREATMENT OF PSORIASIS
`• TREATMENT OF ECZEMA
`• PSORIASIS ASSAY (SCHOLTZ-DUMAS)
`• VC ASSAY (PAIRED COMPARISON)
`• VASOCONSTRICTION ASSAY (S-M)
`
`
`
`<S_MNOm..._O._.Zm_>_._.<mm._.
`
`Emir—Own.“.0._.Zm_2._.<mm._.
`
`(TOPICAL CORTICOSTEROID)
`IN VIVO EXAMPLE:
`
`
`
`E_Omm_._.w00_._.m00._<O_n_0.5
`
`(
`
`(
`
`~
`
`Hm..._n=>_<xmO>_>Z_
`
`
`Aw<S_DD-N._.._OIOwV><ww<992$me
`
`
`=2qu><mw<ZO_._.0_m._.wZOOOw<>
`
`
`AZOwE<n=200Gum—(m:><ww<0>
`
`RELIABILITY
`INCREASING
`
`Gz_w<mm02_
`
`>._._.=m<_._mm
`
`010M
`
`40 0f 50
`
`40 of 50
`
`

`

`COMf"DN PRESERVATIVES
`
`METHYL AND PROPYL PARABENS
`SORBIC ACID
`QUATERNARY AMMONIUM COMPOUNDS
`CBENZALKONIUM CHLORIDE>
`MERCURIALS CTHIMEROSAL>
`BENZVL ALCOHOL
`
`DESIRABLE ATTRIBUTES
`
`l.
`2.
`3.
`4.
`5.
`6.
`7.
`8.
`9.
`
`BROAD SPECTRUM
`RAPID ACTING
`NONALLERGENIC AND NONSENSITIZING
`NONTOXIC AND NONIRRITATING
`COMPATIBILITY
`STABILITY
`SOLUBLE
`ECONOMICAL
`ODORLESS
`
`41 of 50
`
`

`

`Fonmdation R,de Number 2
`
`Better to aJt off ')QI am at the shaJlder fhai to
`use a neN ecipient or solvent in o famJatia,
`when a, dd.' well--=ch:rcclatz.ed a,e v.aJd do as wel
`
`42 of 50
`
`

`

`mJ3
`
`detected.
`solid state transitions of the drug not previously
`Source: Insufficient solubilizer in system and/or
`
`inhomogeneity and variable bioavailability.
`My guess: Physical stability producing product
`
`FAILURE DURING DEVELOPMENT?
`
`MOST LIKELY FORMULATION CAUSE OF PRODUCT
`
`(
`
`(
`
`43 of 50
`
`

`

`INCREASE DRUG TISSUE C~CENTRATIONS (SKIN)?
`INCREASE TOTAL DRUG ABSORPTION?
`
`1
`1 EXTEND DURATION OF CRITICAL TISSUE LEVEL?
`1
`
`SAME FOR TOPICAL AS FOR SYSTEMIC?
`
`INCREASE PEAK ABSORPTION?
`INCREASE STEADY STATE FLUX?
`
`1
`
`1
`• REDUCE LAG TIME?
`1
`
`,
`
`DESIRED ENHANCEMENT EFFECTS?
`
`....
`
`(
`
`44 of 50
`
`

`

`oe
`
`-Products at lower drug concentration use the same
`
`vehicle without modification.
`
`concentration.
`capable of dissolving maximum predicted clinical drug
`
`I. Develop one vehicle with fixed solvent concentration -.
`
`OPTIMIZATION STRATEGIES
`
`(
`
`(
`
`45 of 50
`
`

`

`Flux
`
`Cone. -X/2
`
`Cone. -X
`
`(
`
`(
`
`N\xI.950
`
`fovls." ~ f re£,tj ~J J 1i,. L
`
`t
`
`t
`
`0481
`
`46 0f 50
`
`46 of 50
`
`

`

`09
`
`to totally solubilize the drug.
`optimized by use of slightly more solvent than is needed
`
`II. Each formulation, at different drug concentrations, is
`
`OPTIMIZATION STRATEGIES (Cont'd}
`
`(
`
`\
`/
`
`~
`/
`
`47 of 50
`
`

`

`Flux
`
`Flux
`
`Cone. -X/2
`
`Cone. -X
`
`(
`
`\
`
`0489 4
`
`t
`
`t
`
`8 of 50
`
`48 of 50
`
`

`

`STRATEGY:
`SOLUBILIZE DRUG AT HIGHEST CLINICAL CONC .
`
`OINTMENT
`
`CREAM
`
`VEHICLE .A.
`
`I CONC. = )(
`I CONC. = X
`
`VEHICLE ·a•
`
`I I
`I I
`
`• A.
`
`= x12 I I
`= x12I I
`
`·e·
`
`.A.
`
`:)(/3 I
`
`= )(/31
`·a·
`
`1) IN VITRO FLUX, EXCISED HUMAN SKIN, ALL ABOVE.
`
`2) MEASURE SYSTEMIC ABSORPTION FOLLOW I NG
`TOPICAL ADMINISTRATION IN ANIMAL (DOG,
`MONKEY?) W 1TH CONC. X.
`
`CONDUCT CHRONIC TOXICOLOGY IN ANIMALS, AND HUMAN
`STUDIES AS REQUIRED, WITH VEHICLE SHOWING THE
`GREATEST AISORPTION, CONC. X.
`
`49 of 50
`
`

`

`8. Vehicle: Aa complex 88 neceaaary, 88 simple 88 poaalble.
`
`Oll)t
`
`7. Product atablllty, for both drug and system. la 88 Important 88 any other
`
`product parameter. (Don't forget use teats and shipping teats)
`
`6. Understand, and respect. physician and patient preferencaa.
`
`6. Solublllze drug. If poaalble.
`
`4. Adequate product preservation.
`
`a Minimum drug concentration.
`2. Minimize toxicity of the product (Prudent exclplent. solvent selection).
`
`1. Normal objective la to maximize drug flux Into the akin.
`
`TOPICAL PRODUCT OPTIMIZATION
`
`(
`
`(
`
`(
`
`50 of 50
`
`